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FLASH GENE
Symbol NPC1L1 contributors: mct - updated : 25-10-2012
HGNC name NPC1 (Niemann-Pick disease, type C1, gene)-like 1
HGNC id 7898
DNA
TYPE functioning gene
STRUCTURE 28.79 kb     20 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Binding site
text structure
  • a sterol regulatory element,transcription factor binsding sites
  • important HNF1 binding site was identified within the NPC1L1 promoter and HNF1A can bind to the NPC1L1 promoter
  • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 - 5066 148.7 1359 - 2010 20307540
    - - 2840 - - - 2004 15173162
    also called delta exon 5
    - - 2570 80 724 - 2004 15173162
  • also called NPC1L1T
  • skipping exon 7 terminating in exon 8
  • 19 - 4985 - 1332 - 2010 20307540
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivegallbladder    
     intestinesmall intestine  highly Homo sapiens
     liver   highly Homo sapiens
     stomach    
    Endocrinepancreas    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveenterocyte
    Lymphoid/Immunehistiocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal domain (NTD) of NPC1L1 binds cholesterol
  • conserved N-terminal “NPC1” domain, encompassing a similar cysteine-rich globular domain
  • sterol sensing domain (SSD)
  • YQRL motif, but lacking the dileucine targeting motif of NPC1
  • a typical signal peptide and 13 membrane-spanning domains, 5 of the 13 membrane-spanning helices constitute a predicted sterol sensing domain (SSD) encompassing 180 AAs, that may be involved in sterol binding
  • extensive N-linked glycosylation sites
  • C-terminus projects to the cytosol
  • HOMOLOGY
    interspecies homolog to NPC1
    homolog to SCAP
    ortholog to HMGCR
    Homologene
    FAMILY
  • lipid transport facilitators family
  • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • enriched in the apical membrane of small intestine absorptive enterocytes where it mediates extracellular sterol transport across the brush border membrane
  • dynamic trafficking of NPC1L1 between the cell surface and intracellular compartments and suggests that this transport is involved in NPC1L1-mediated cellular sterol uptake
  • can move between the endocytic recycling compartment (ERC)4 and plasma membrane (PM)
  • localizes on the brush border membrane of small intestine and canalicular membrane of liver
  • basic FUNCTION
  • involved in intestinal absorption and intracellular cholesterol transport
  • required for intestinal uptake of both cholesterol and phytosterols and playing a major role in cholesterol
  • involved in an ezetimibe-sensitive pathway for cholesterol uptake
  • has the ability to transport alpha-tocopherol
  • play an essential role in intestinal cholesterol absorption
  • mediates cholesterol uptake through vesicular endocytosis, and NPC1L1 recycles between endocytic recycling compartment (ERC) and plasma membrane (PM) in responding to cellular cholesterol alterations
  • mediates intestinal cholesterol absorption and it may also limit hepatobiliary cholesterol excretion
  • essential protein for dietary cholesterol absorption
  • mediates cholesterol uptake via vesicular endocytosis
  • playing a crucial role in dietary and biliary cholesterol absorption
  • senses cholesterol through direct binding by its NTD, then cholesterol may be transferred to local membrane to form the NPC1L1-flotillin-cholesterol membrane microdomain, which is internalized via the clathrin-AP2 pathway
  • function of NPC1L1 in reabsorbing biliary cholesterol was impaired when hepatic CDC42 was deleted
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cellular trafficking transport
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • NR1H3 target gene further supporting a crucial role of NR1H3 in intestinal cholesterol homeostasis
  • functional role of FLOT1, FLOT2 in NPC1L1-mediated cholesterol uptake, elucidating the formation of NPC1L1-FLOT1, FLOT2-positive cholesterol-enriched membrane microdomains as a mechanism for efficient cholesterol absorption
  • CDC42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption
  • apical PYY was able to decrease cholesterol uptake via NPC1L1 downregulation
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
  • to poor LDL-C response to treatment with ezetimibe co-administrated with statin
  • to low absorption of cholesterol
  • to hypercholesterolemia
  • Variant & Polymorphism SNP , other
  • associated to poor LDL-C response to treatment with ezetimibe co-administrated with statin
  • variants associated with reduced sterol absorption and plasma low-density lipoprotein levels
  • NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    metabolismlipidcholesterol
    useful drug target for the treatment of hypercholesterolemia and sitosterolemia
    diabetemetabolic syndrom 
    NPC1L1 inhibition has been shown to have beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis
    ANIMAL & CELL MODELS
    NPC1L1-deficient mice show dramatic reductions in dietary cholesterol absorption